1. Field of the Invention
The invention relates to syntheses for preparing 1,4-diketopyrrolo[3,4-c]pyrroles useful as pigments or intermediates in the coloration of plastics, paints and printing inks.
2. Description of Related Art
A variety of syntheses exist in the prior art for the preparation of 1,4-diketopyrrolo[3,4-c]pyrroles of the general formula: 
wherein R1 to R4 are commonly used substituent groups such as alkyl or hydrogen. For example, U.S. Pat. No. 4,415,685 discloses preparing a 1,4-diketopyrrolo[3,4-c]pyrrole, where R1 and R3 are hydrogen and R2 and R4 are phenyl, by heating benzonitrile with bromoacetic ester and zinc in toluene. Alternatively, 1,4-diketopyrrolo [3,4-c]pyrrole derivatives where R2 and R4 are different and prepared by subsequently introducing the substituent groups or by converting pre-existing precursor substituent groups via halogenation, acylation, sulfochlorination, etc. which may be followed by reaction of the sulfochloride, for example with an amine, alcohol or phenol.
U.S. Pat. No. 4,579,949 describes a process for preparing structurally similar pyrolopyrroles where R2 and R4 are each independently isocyclic or heterocyclic aromatic radicals by reacting disuccinate with a nitrile of the general formula R2xe2x80x94CN or R4xe2x80x94CN in an organic solvent and strong base at elevated temperatures followed by a hydrolysis step.
U.S. Pat. No. 4,931,566 represents an improvement over the process described in U.S. Pat. No. 4,579,949 wherein the hydrolysis step is carried out in stages.
U.S. Pat. No. 4,659,775 describes a process for preparing these pyrrolopyrroles by reacting an amino ester or pyrrolinone containing the R2 substituent with a nitrile of the general formula R4xe2x80x94CN, where R4 represents an alkyl or aralkyl group or an isocyclic or heterocyclic or aromatic radical, in a strong base and an organic solvent.
U.S. Pat. No. 4,585,878 describes two processes for preparing N-substituted 1,4-diketopyrrolo[3,4-c]pyrroles. The first involves reacting a 1,4-diketopyrrolo [3,4-c]-pyrrole, where R1 and R3 are hydrogen, with a compound containing the radicals replacing R1 and R3 as leaving groups, in an organic solvent. The second method involves reacting a compound of the formula R2xe2x80x94CHxe2x95x90Nxe2x80x94R3 or R4xe2x80x94CHxe2x95x90Nxe2x80x94R1 or both with a succinic acid diester in a base and organic solvent, then dehydrogenating the resulting product.
An object of the present invention is to provide an m improved synthesis for preparing asymmetrical or symmetrical 1,4-diketo pyrrolo[3,4-c]pyrroles from one or more xcex2-ketoamides.
The first synthesis of the present invention involves a reaction between a halogenated xcex2-ketoamide and an alkaline metal or alkaline earth salt of a xcex2-ketoamide to produce a succinamide, which is then heated in the presence of a Lewis Acid or acid chloride to produce a 1,4-diketopyrrolo[3,4-c]pyrrole.
The second synthesis of the present invention involves an oxidative dimerization of an alkali metal or alkaline earth salt of a xcex2-ketoamide to form a succinamide, which is then heated in the presence of a Lewis Acid or acid chloride to produce a 1,4-diketopyrrolo[3,4-c]pyrrole. diketopyrrolo[3,4-c]pyrrole.
An advantage of the syntheses of the present invention is the flexibility, in that a wide variety of either symmetrical or asymmetrical 1,4-diketopyrrolo[3,4-c]pyrroles can be produced.
In one aspect, the present invention relates to a synthesis for preparing asymmetrical or symmetrical 1,4-diketo pyrrolo[3,4-c]pyrrole of formula I: 
wherein R1, R2, R3 and R4 are each independently selected from hydrogen, C1-C2alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals comprising the steps of:
(a) reacting a xcex2-ketoamide of either formula II: 
or wherein R2 and R4 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals or a xcex2-ketoamide of formula III: 
wherein R2 and R1 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals, with a strong base to form an alkali metal or alkaline earth salt;
(b) halogenating xcex2-ketoamide of formula II or formula III, thereby forming a halogenated xcex2-ketoamide;
(c) reacting said alkali or alkaline earth metal salt with said halogenated xcex2-ketoamide, thereby forming a succinamide of the formula VI: 
wherein R1 and R2 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals;
(d) heating the succinamide of Formula IV in the presence of a Lewis acid or acid chloride.
In another aspect, the present invention relates to a synthesis for preparing a symmetrical 1,4-diketopyrrolo[3,4-c]pyrrole conforming to formula V: 
wherein R1 and Rs are as previously defined; comprising the steps of:
(a) reacting a xcex2-ketoamide conforming to formula II: 
wherein R4 and R1 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals with a strong base to form an alkali or alkaline earth metal salt;
(b) oxidatively dimerizing said alkali or alkaline earth metal salt, thereby forming a succinamide of formula VI: 
wherein R1, R2, R3 and R4 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals; and
(c) heating said succinamide of formula IV in the presence of a Lewis Acid or acid chloride to effect ring closure.
Step (a) of the asymmetrical of symmetrical synthesis of the present invention comprises reacting a xcex2-ketoamide conforming to either formula II or III with a strong base to form an alkali metal or alkaline earth metal salt xcex2-ketoamide. This reaction IV may be conducted in a non-reactive organic solvent at temperatures of from about 20 to about 140xc2x0 C., more preferably 20 to 100xc2x0 C. The particular temperature employed for forming of the metal xcex2-ketoamide salt will depend on the temperature required to solubilize the amide.
Suitable non-reactive organic solvents include n-octane, n-decane, benzene, ethylbenzene, toluene, xylene, chlorobenzene, decalin and the like.
As for the strong base, examples include alkali metal hydroxides such as sodium, potassium and lithium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal amides such as sodium, potassium and lithium amide, diethylamide, diisopropylamide or isopropylcyclo-hexylamide; and alkali metal hydrides such as sodium, potassium or lithium hydride, as well as alkali metal or alkaline earth metal alcoholates derived from primary, secondary or tertiary C1-C10 alcohols e.g. sodium, potassium or lithium methylate, ethylate, n-propylate, isopropylate, n-butylate, sec-butylate, tert-butylate, 2-methyl-2-butylate, 2-methyl-2-pentylate, 3-methyl-3-pentylate, 3-ethyl-pentylate, or alkali metal or alkaline earth metal phenolates, o-alkyl substituted phenolates, such as sodium or potassium o-cresolate.
It is preferred to use an alkali metal amide, hydride or alcoholate to form the metal amide salt and it is particularly preferred that the alkali metal be sodium or potassium. If alcoholates are employed, it is preferred that the alcohol moiety be derived from a secondary or tertiary alcohol such as isopropyl alcohol, sec- or tert-butyl alcohol and tert-amyl alcohol. If desired, the alkali metal alcoholates may be prepared in situ by reacting the appropriate alcohol with the desired alkali metal, alkali metal hydride or alkali metal amide.
The starting material for step (a) of the first synthesis is a xcex2-ketoamide of either formula II: 
or formula III: 
where R1, R2, R3 and R4 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocycloic or heterocyclic aromatic radicals.
An important advantage of the syntheses disclosed herein is that they are very versatile. More particularly, the choice of the C1-C20 radicals for R1, R2, R3 and R4 is virtually unlimited. Such choices include substituted and unsubstituted straight and branched chain, saturated or unsaturated alkyls, cycloalkyls, aralkyls, isocyclic aromatic and heterocyclic aromatic radicals. Preferably, R1 and R3 are independently selected from hydrogen, C6-C14 aryl or aralkyl radicals and R2 and R4 are independently selected from C6-C14 aryls or aralkyl radicals.
As alkyl radicals, the preferable choices are C1-C10 alkyl radicals especially preferred are C1-C16 alkyl radicals such as methyl, ethyl, isopropyl, sec-butyl, tert-butyl, tert-amyl, cyclohexyl, octyl, decyl, dodecyl, stearyl and the like. The aralkyl radical substituents are preferably those which contain a branched or unbranched C1-C12 alkyls or alkenyls preferably C1-C6 and especially preferred are C1-C4 and mono- to tetra-cyclic aryl radicals, e.g. benzyl, phenylethyl, etc.
The isocyclic aromatic radical substituents may be mono- to tetra-cyclic radicals, e.g. phenyl, biphenyl, naphthyl, etc. In the case of the heterocyclic aromatic radicals, they may be mono-, di- or tri-cyclic and may be purely heterocyclic, e.g. O-heterocyclic, N-heterocyclic or S-heterocyclic or may contain one or more fused benzene rings, examples include pyridyl, pyrimidyl, pyrazinyl, triazinyl, furyl, pyrrolyl, thiophenyl, quinolyl, coumarinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, dibenzfuranyl, benzothiophenyl, dibenzothiophenyl, indolyl, carbazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, indazolyl, benzthiazolyl, pyridazinyl, cinnolyl, quinazolyl, quinoxalyl, phthalazinyl, phthalazindionyl, phthalamidyl, chromonyl, naphtholactamyl, quinolonyl, o-sulfobenzimidyl, maleinimidyl, naphtharidinyl, benzimidazolonyl, benzoxazolonyl, benzthiazolonyl, benzthiazothionyl, quinazolonyl, quinoxalonyl, phthalazonyl, dioxopyrimidinyl, pyridonyl, isoquinolonyl, isoquinolinyl, isothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolonyl, acridinyl, acridonyl, quinazolindionyl, quinoxalindionyl, benzoxazindionyl, benzoxazinonyl and naphthalimidyl.
Both the isocyclic and heterocyclic aromatic radicals may contain the customary substituents such as halogen atoms; branched or unbranched C1-C20 alkyl groups which in turn may contain substituents such as halogen, hydroxyl, cyano, xe2x80x94OCOR, xe2x80x94OR, xe2x80x94COOR, xe2x80x94CONR, xe2x80x94Rxe2x80x94OCONHR, etc.; ether groups; mercapto groups; cyano; amino groups; ester groups; ketone groups; amide groups; urethane groups; ureido groups; sulfonylamino groups; sulfonyl groups; carbamoyl groups; xe2x80x94SO2R groups; sulfamoyl groups and the like.
The xcex2-ketoamide starting materials may be prepared by several known methods. For example, suitable xcex2-ketoamide may be prepared by reaction of an appropriate xcex2-keto ester and an appropriate primary amine. A suitable xcex2-keto ester would have a chemical structure conforming to formula VIII: 
where R2 has the same definition as R2 in formula III, and Rxe2x80x2 is a C1-C20 branched or straight alkyl radical such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, n-amyl, isoamyl, n-octyl, n-decyl, isodecyl, dodecyl and hexadecyl; and more preferably is a C1-C6 straight chain radical such as methyl, ethyl, propyl or isopropyl.
xcex2-keto esters may be prepared by the well-known Claison Acylation, illustrated by the reaction:
(R2)COCH3+(R1)2COxe2x86x92(R2)COCH2CO2(R1)+(R1)OH
where R1 and R2 are as defined above.
The xcex2-keto ester may be reacted with a primary amine having the formula H2N-R3, where R3 is as defined in formula III above, to produce the desired xcex2-ketoamide. The reaction of the xcex2-keto ester and primary amine may be performed at temperatures of from about 40xc2x0 to about 150xc2x0 C., more preferably from about 60xc2x0 to about 100xc2x0 C., and in the presence of a non-reactive aliphatic or aromatic solvent. The reaction typically has a duration of about 0.5 to 3 hours.
Suitable non-reactive aliphatic or aromatic solvents include hydrocarbons such as n-octane, n-decane, benzene, a toluene, ethylbenzene, chlorobenzene, xylene and decalin.
Alternatively, the desired xcex2-ketoamide starting material may be prepared by reacting a ketone and an isocyanate as illustrated below:
R2COCH3+Oxe2x95x90Cxe2x95x90NR3xe2x86x92xcex2-ketoamide
wherein R2 and R3 are as previously defined.
The reaction of the ketone and the isocyanate is typically performed in the presence of a non-reactive diluent.
Step (b) of the first synthesis comprises halogenating a xcex2-ketoamide of either formula II or formula III which was not converted into an alkali metal or alkaline earth metal salt in step (a) above, thereby forming a halogenated xcex2-ketoamide conforming to either formula IX: 
or formula X: 
where R1, R2, R3 and R4 have the same definitions as in formulae II and III, respectively, and X is a halogen such as fluorine, chlorine, bromine or iodine.
The halogenating agent may be chlorine, bromine or iodine and the halogenation reaction may be performed at temperatures of about 40xc2x0 to about 150xc2x0 C. in the presence of an inert solvent. Suitable examples of inert solvents include carboxylic acids and esters such as acetic acid and ethyl acetate; C1-C6 alcohols such as methanol, ethanol, isopropanol and sec-butanol; and hydrocarbons such as hexane, benzene and chlorobenzene.
Step (c) of the first synthesis comprises reacting the alkali or alkaline earth metal salt formed in step (a) with the halogenated xcex2-ketoamide formed in step (b), thereby forming a succinamide conforming to formula IV: 
wherein R1, R2, R3 and R4 are as previously defined.
This reaction readily takes place at temperatures ranging from about 40xc2x0 to about 150xc2x0 C. and in the presence of a non-reactive solvent such as n-octane, n-decane, benzene, toluene, ethylbenzene, xylene, chlorobenzene, and decalin.
Step (d) of the first synthesis is a ring closure reaction which comprises heating the succinamide produced in step (c) in the presence of a Lewis Acid or acid chloride to thereby produce a 1,4-diketopyrrolo[3,4-c]pyrrole. The reaction will be generally carried out at temperatures ranging from about 80 to about 250xc2x0 C., more preferably from about 100 to about 220xc2x0 C., in the presence of a non-reactive organic solvent such as n-octane, n-decane, benzene, toluene, dimethyl formamide, dihydroxyacetone, sulfolene, ethylbenzene, xylene, chlorobenzene and decalin. The preferable Lewis Acid is zinc chloride, zinc acetate, aluminum trichloride or boron trifluoride; the preferred acid chloride is a C6-C14 sulfonyl chloride, phosphorus oxychloride or phosphoryl bromide.
The synthesis described above will produce an xe2x80x9casymmetricalxe2x80x9d 1,4-diketopyrrolo[3,4-c]pyrrole in which R2 and R4 are always different. One of ordinary skill in the art will readily understand that a xe2x80x9csymmetricalxe2x80x9d 1,4-diketopyrrolo[3,4-c]pyrrole may be prepared if a single xcex2-ketoamide (i.e., where R2 is identical to R4) is employed for both step (a) and step (b)
The present invention includes a second synthesis directed to the preparation of a symmetrical 1,4-diketopyrrolo[3,4-c]pyrrole conforming to formula V: 
wherein R1and R2 are independently selected from hydrogen or a C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals. This second synthesis includes the steps of:
(a) reacting a xcex2-ketoamide conforming to formula VI: 
wherein R2 and R1 are each independently selected from hydrogen, C1-C20 alkyls, cycloalkyls, aralkyls, or isocyclic or heterocyclic aromatic radicals; with a strong base to form the corresponding alkali metal or alkaline earth salt;
(b) oxidatively dimerizing the alkali metal or alkaline earth salt to form a succinamide conforming to formula VI: 
wherein R1 and R2 are as previously defined;
(c) heating said succinamide in the presence of a Lewis Acid or an acid chloride to thereby produce a symmetrical 1,4-diketopyrrolo[3,4-c]pyrrole.
Step (a) of the second synthesis corresponds to step (a) of the first synthesis of the present invention.
Step (b) of the second synthesis may be performed using a halogen such as chlorine, bromine or iodine at temperatures of from about 20xc2x0 to about 100xc2x0 C., preferably from about 20xc2x0 to 60xc2x0 C. The reaction is preferably carried out in the presence of a non-reactive solvent such as n-hexane, n-octane, n-decane, cyclohexane, benzene, toluene, xylene, ethylbenzene, chlorobenzene and decalin.
Step (c) of the second synthesis involves heating the succinamate resulting from step (b) as described in step (d) of the first synthesis.
The 1,4-diketopyrrolo[3,4-c]pyrroles which may be prepared by the syntheses of the present invention are useful as pigments and pigment intermediates for coloring plastics, resins, paints, lacquers and printing inks using techniques and apparatus well known to those of ordinary skill in this art.